CN116617468A - Heart stent and preparation method and application thereof - Google Patents
Heart stent and preparation method and application thereof Download PDFInfo
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- CN116617468A CN116617468A CN202310520622.6A CN202310520622A CN116617468A CN 116617468 A CN116617468 A CN 116617468A CN 202310520622 A CN202310520622 A CN 202310520622A CN 116617468 A CN116617468 A CN 116617468A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/041—Mixtures of macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/146—Porous materials, e.g. foams or sponges
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially resorbable by the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/422—Anti-atherosclerotic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2420/00—Materials or methods for coatings medical devices
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Surgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention relates to the field of stents, in particular to a heart stent, and a preparation method and application thereof. The preparation method of the heart stent comprises the following steps: adding a cross-linking agent into a mixed system of a polylactic acid solution and a collagen solution, and then performing a cross-linking reaction to obtain printing slurry; printing and forming the printing paste into the heart stent; wherein the molecular weight of the polylactic acid in the polylactic acid solution is 30 ten thousand to 100 ten thousand. The heart stent prepared by the method has better mechanical property and degradation property, higher supporting force, biological safety and biocompatibility and stable degradation rate.
Description
Technical Field
The invention relates to the field of stents, in particular to a heart stent, and a preparation method and application thereof.
Background
The main manifestation of coronary artery disease is the presence of atheromatous plaque on the vessel lumen wall, and the longer the time, the more plaque becomes, causing stenosis and blockage of the vessel lumen. For treating the diseases, a heart stent, which has the function of dredging arterial blood vessels, is developed, and is often used for treating coronary heart diseases.
Currently, cardiac stents are mainly classified into three types, namely, metal stents, drug-coated stents and biodegradable stents. Wherein, the traditional metal stent generates late inflammation such as restenosis in the stent, and the restenosis is mainly caused by vascular endothelial injury in the implantation and migration processes of the stent, stimulates smooth muscle cells and extracellular matrix proliferation, and promotes neointimal hyperplasia. The biodegradable stent can be automatically dissolved in the body after the stent is acted and absorbed by the body, so that adverse effects caused by the long-term storage of the stent in the body are avoided. Therefore, biodegradable stents are an important research direction in the current cardiac stent field. Biodegradable stents are being developed in two general categories, biodegradable polymer stents and degradable metal and alloy stents. The body material of the biodegradable polymer stent mainly comprises polyesters, including Polycaprolactone (PCL), poly-L-lactic acid (PLLA), poly-racemlactic acid (PDLLA) and the like; the degradable metal bracket mainly comprises magnesium, iron, zinc and alloys thereof. Among various materials, polylactic acid has excellent biocompatibility and good degradation performance and mechanical properties, and thus is widely used. But the polylactic acid with different molecular weights and different structures has larger performance difference, and the selection or preparation of the polylactic acid suitable for the heart stent is still the current research focus.
The conventional method for preparing polylactic acid is to compound three kinds of polylactic acid of high molecular weight left-handed polylactic acid, low molecular weight left-handed polylactic acid and high molecular weight racemized polylactic acid, so that the degradation time is shortened while the mechanical strength of the high molecular weight left-handed polylactic acid is maintained, and the prepared scaffold has good mechanical strength, biocompatibility and biodegradability. However, since the raw materials used in the method are polylactic acid, acidic substances generated in the metabolic process of the polylactic acid are easy to cause inflammatory reaction of organisms; the strong hydrophobicity of polylactic acid can influence the blood compatibility of the stent, and the risk of thrombus generation is increased; in addition, the stent prepared by the method still has the problems of insufficient strength and lower supporting force, is easy to retract in the process of vasoconstriction and expansion, and has insufficient overall biological safety.
In view of this, the present invention has been made.
Disclosure of Invention
One aspect of the invention relates to a method for preparing a cardiac stent, comprising the steps of:
adding a cross-linking agent into a mixed system of a polylactic acid solution and a collagen solution, and then performing a cross-linking reaction to obtain printing slurry; printing and forming the printing paste into the heart stent;
wherein the molecular weight of the polylactic acid in the polylactic acid solution is 30 ten thousand to 100 ten thousand.
The heart stent prepared by the method has better mechanical property and degradation property, higher supporting force, biological safety and biocompatibility and stable degradation rate.
The invention also relates to the heart stent prepared by the preparation method of the heart stent.
The heart stent has better mechanical property and degradation property, stable degradation rate and can be completely degraded in vivo; has high supporting force, biological safety and biocompatibility, and the metabolic process in the body is not easy to induce inflammatory reaction.
In another aspect, the invention also relates to the use of the cardiac stent in the manufacture of a medicament or medical device for the treatment or prophylaxis of coronary artery disease.
Compared with the prior art, the invention has the beneficial effects that:
(1) According to the preparation method of the heart stent, the polylactic acid and the collagen with certain molecular weights are crosslinked, and the obtained printing slurry is printed and molded to obtain the heart stent.
(2) The heart stent provided by the invention has excellent mechanical property and degradation property, stable degradation rate and capability of being completely degraded in vivo; the support force, the biological safety and the biocompatibility are high, and the inflammatory reaction is not easy to be caused in the metabolic process in vivo; the radial strength is 196-254 kPa, the porosity is 23.0-44.7%, and the degradation time is 12-24 months.
Detailed Description
The technical solution of the present invention will be clearly and completely described in conjunction with the specific embodiments, but it will be understood by those skilled in the art that the examples described below are some, but not all, examples of the present invention, and are intended to be illustrative only and should not be construed as limiting the scope of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
One aspect of the invention relates to a method for preparing a cardiac stent, comprising the steps of:
adding a cross-linking agent into a mixed system of a polylactic acid solution and a collagen solution, and then performing a cross-linking reaction to obtain printing slurry; printing and forming the printing paste into the heart stent;
wherein the molecular weight of the polylactic acid in the polylactic acid solution is 30 ten thousand to 100 ten thousand (for example, 30 ten thousand, 35 ten thousand, 40 ten thousand, 45 ten thousand, 50 ten thousand, 55 ten thousand, 60 ten thousand, 65 ten thousand, 70 ten thousand, 75 ten thousand, 80 ten thousand, 85 ten thousand, 90 ten thousand, 95 ten thousand or 100 ten thousand).
According to the preparation method of the heart stent, polylactic acid and collagen with certain molecular weight are crosslinked, and the obtained printing slurry is printed and molded to obtain the heart stent.
According to the invention, after the polylactic acid is subjected to further crosslinking reaction in the collagen solution, the acidic self-catalysis effect of the polylactic acid in the self-degradation process is avoided, so that the degradation speed of the polylactic acid is too high, the control is not easy, and the degradation period is uncertain. And also avoids serious local ponding caused by acidic substance accumulation in the degradation process when polylactic acid is used as a receptor to be placed in a human body. The polylactic acid can improve the defects of polylactic acid (PLA) through further crosslinking reaction in the collagen solution, and mainly improves the hydrophilic performance, the cell compatibility, the degradation performance, the mechanical strength and other performances of the polylactic acid. The polylactic acid and the collagen cooperate, so that the heart stent has higher strength, proper degradation rate and higher biological safety.
The composite material formed after the preparation has the advantages that the surface hydrophobicity of the polylactic acid is strong, the biocompatibility of the polylactic acid is reduced, the hydrophilicity of the polylactic acid is improved through the crosslinking of the polylactic acid and the collagen, and the biocompatibility is enhanced; the degradation period of polylactic acid in a human body is difficult to control, and excessive accumulation of acidic degradation products leads to excessive local acidity and non-infectious inflammation to occur in an implanted part and local severe ponding, so that the integral modification of the polylactic acid improves the toughness and the stable degradation rate.
Preferably, the preparation method of the polylactic acid in the polylactic acid solution comprises the following steps:
adding stannous octoate into the dehydrated levolactic acid monomer, and then carrying out distillation, condensation, water washing and recrystallization to obtain the levolactic acid;
carrying out ring-opening polymerization reaction on the mixed system of the levorotatory lactide and the zinc acetylacetonate in a protective atmosphere; centrifuging the product of the ring-opening polymerization reaction, uniformly mixing the supernatant obtained by the centrifugation with methanol, and then filtering, washing and drying.
Preferably, the mass ratio of the levolactic acid monomer to the stannous octoate is 1: 1-10 (e.g., 1:1, 1:3, 1:5, 1:7, 1:9, or 1:10).
Preferably, the mass ratio of the levorotatory lactide to the zinc acetylacetonate is 1:0.5 to 1.5 (e.g., 1:0.5, 1:0.7, 1:0.9, 1:1.1, 1:1.3, or 1:1.5).
Preferably, the distillation temperature is 180-220 ℃ (e.g. 180 ℃, 185 ℃, 190 ℃, 195 ℃, 200 ℃, 205 ℃, 210 ℃, 215 ℃ or 220 ℃).
Preferably, the pressure of the distillation is from 0.1 to 1.0kPa (e.g., 0.1kPa, 0.2kPa, 0.3kPa, 0.4kPa, 0.5kPa, 0.6kPa, 0.7kPa, 0.8kPa, 0.9kPa, or 1.0 kPa).
Preferably, the temperature of the ring-opening polymerization reaction is 100 to 160 ℃ (e.g., 100 ℃, 105 ℃, 110 ℃, 115 ℃, 120 ℃, 125 ℃, 130 ℃, 135 ℃, 140 ℃, 145 ℃, 150 ℃, 155 ℃, or 160 ℃).
Preferably, the ring-opening polymerization reaction is carried out for a period of 8 to 48 hours (e.g., 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, 28 hours, 32 hours, 36 hours, 40 hours, 44 hours, or 48 hours).
The polylactic acid with proper molecular weight is prepared by the coordination ring-opening polymerization method, the molecular weight distribution of the obtained polylactic acid is relatively symmetrical and the selectivity is relatively good, the problems of too slow degradation rate caused by too high molecular weight of the polylactic acid and low strength caused by too low molecular weight of the polylactic acid are avoided, and the prepared polylactic acid has better mechanical property and degradation property.
According to the invention, the collagen and the polylactic acid are uniformly mixed, so that the strength and the hydrophilicity of the polylactic acid are effectively improved, and the prepared heart stent has higher supporting force and biological safety so as to meet the requirements of practical application.
According to the invention, by blending the collagen and the polylactic acid, the polylactic acid can be hydrophilically modified by utilizing the excellent hydrophilia of the collagen, so that the blood compatibility of the stent is improved, the generation of thrombus is reduced, and the prepared heart stent has higher biocompatibility.
Preferably, the concentration of polylactic acid in the polylactic acid solution is 0.01 to 0.2mg/ml (e.g., 0.01mg/ml, 0.05mg/ml, 0.1mg/ml, 0.15mg/ml, or 0.2 mg/ml).
Preferably, the concentration of collagen in the collagen solution is 0.3 to 1.0mg/ml (e.g., 0.3mg/ml, 0.5mg/ml, 0.7mg/ml, 0.9mg/ml, or 1.0 mg/ml).
Preferably, the mass ratio of the polylactic acid and the collagen in the polylactic acid solution is 0.02-0.2: 1 (e.g., 0.02:1, 0.04:1, 0.06:1, 0.08:1, 0.1:1, 0.12:1, 0.14:1, 0.16:1, 0.18:1, or 0.2:1).
Preferably, the dehydration temperature of the L-lactic acid monomer is 170-220 ℃ (e.g., 170 ℃, 180 ℃, 190 ℃, 200 ℃, 210 ℃ or 220 ℃).
Preferably, the dehydration time of the L-lactic acid monomer is 5 to 10 hours (e.g., 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours).
Preferably, the dehydration pressure of the L-lactic acid monomer is 5kPa.
Preferably, the preparation method of the collagen comprises the following steps:
immersing fresh animal tissue in glacial acetic acid with the volume concentration of 8-12% (such as 8%, 9%, 10%, 11% or 12%) for 180-270 hours (such as 180 hours, 190 hours, 200 hours, 210 hours, 220 hours, 230 hours, 240 hours, 250 hours, 260 hours or 270 hours), removing horny layer and fat layer, adding 0.3-3 wt% (such as 0.3wt%, 0.5wt%, 0.7wt%, 0.9wt%, 1.3wt%, 1.6wt%, 1.9wt%, 2.2wt%, 2.5wt%, 2.8wt% or 3 wt%) pepsin into 0.3-0.7M (such as 0.3M, 0.4M, 0.5M, 0.6M or 0.7M) glacial acetic acid solution, and performing enzymolysis digestion for 96-120 hours (such as 96 hours, 100 hours, 104 hours, 108 hours, 112 hours, 116 hours or 120 hours) to obtain collagen enzymolysis solution;
and inactivating, redissolving, salting out and purifying the collagen enzymolysis liquid to obtain the collagen solution.
Preferably, the concentration of the collagen in the printing paste is 10 to 40mg/ml (e.g., 10mg/ml, 15mg/ml, 20mg/ml, 25mg/ml, 30mg/ml, 35mg/ml, or 40 mg/ml).
Preferably, the temperature of the crosslinking reaction is 15 to 30 ℃ (e.g., 15 ℃, 20 ℃, 25 ℃, or 30 ℃).
Preferably, the time of the crosslinking reaction is 8 to 24 hours (e.g., 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, or 24 hours).
Preferably, the crosslinking agent comprises: 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and/or N-hydroxysuccinimide (NHS).
Preferably, the concentration of EDC is 10 to 80mM (e.g., 10mM, 20mM, 30mM, 40mM, 50mM, 60mM, 70mM, or 80 mM).
Preferably, the concentration of NHS is 2-50 mM (e.g., 2mM, 5mM, 10mM, 15mM, 20mM, 25mM, 30mM, 35mM, 40mM, 45mM, or 50 mM).
Preferably, the preparation method of the heart stent further comprises the following steps: the cardiac stent is freeze-dried and drug-coated.
The invention enables the heart stent to have a porous structure by a freeze drying method, can effectively improve the drug carrying capacity of the heart stent, and enables the drug to be slowly released in the body, thereby further improving the biological safety of the stent.
Preferably, the drug-coated drug types include: at least one of rapamycin, paclitaxel, heparin, or aspirin.
Preferably, the drug-coated drug concentration is 0.08 to 0.12g/mL (e.g., 0.08g/mL, 0.09g/mL, 0.1g/mL, 0.11g/mL, or 0.12 g/mL).
The invention also relates to the heart stent prepared by the preparation method of the heart stent.
The heart stent has better mechanical property and degradation property, stable degradation rate, can be completely degraded in vivo, and the degradation products are absorbable substances harmless to human bodies; the support force, the biological safety and the biocompatibility are high, and the inflammatory reaction is not easy to be caused in the metabolic process in vivo; the radial strength is 196-254 kPa, the porosity is 23.0-44.7%, and the degradation time is 12-24 months.
In another aspect, the invention also relates to the use of the cardiac stent in the manufacture of a medicament or medical device for the treatment or prophylaxis of coronary artery disease.
Embodiments of the present invention will be described in detail below with reference to specific examples and comparative examples.
Example 1
1. The preparation of polylactic acid comprises the following steps:
(1) Heating and decompressing a levolactic acid monomer at 195 ℃ under 5kPa for dehydration for 8 hours, adding 6wt% of stannous octoate as a catalyst, distilling lactide at 200 ℃ under 0.5kPa, and condensing to obtain crude lactide;
(2) Washing and recrystallizing the crude lactide in sequence to obtain purified levorotatory lactide;
(3) Adding 1.0wt% of zinc acetylacetonate as a catalyst into the purified levorotatory lactide, heating to 130 ℃ in nitrogen atmosphere, and maintaining for 28 hours to perform ring-opening polymerization reaction; centrifuging the product obtained by the ring-opening polymerization reaction, pouring the supernatant into a methanol solution, filtering, washing and drying after the product is fully separated out, thus obtaining the polylactic acid.
2. The preparation of the collagen solution comprises the following steps:
(1) Fresh animal tissues are soaked in 10% glacial acetic acid for 225 hours, then horny layer and fat layer are removed, 1.65wt% pepsin is added into 0.5M glacial acetic acid solution for enzymolysis and digestion for 108 hours, and then collagen enzymolysis liquid is obtained.
(2) And inactivating, redissolving, salting out and purifying the collagen enzymolysis liquid to obtain a collagen solution.
3. The preparation of the heart stent comprises the following steps:
(1) Dissolving the prepared polylactic acid in 1, 4-dioxane, and fully stirring for later use;
(2) Adding the polylactic acid solution into the collagen solution, fully stirring and mixing, and adding a cross-linking agent to carry out a cross-linking reaction at room temperature to prepare printing slurry; the mass ratio of the polylactic acid in the polylactic acid solution to the collagen in the collagen solution is 0.11:1, a step of; the temperature of the crosslinking reaction is 23 ℃; the time of the crosslinking reaction is 16 hours;
(3) Forming the printing slurry into a heart stent by adopting a 3D printing technology, and freeze-drying the heart stent; immersing the freeze-dried heart stent into a drug solution with a preset concentration, and taking out and drying after full immersion.
Example 2
1. The preparation of polylactic acid comprises the following steps:
(1) Heating and decompressing a levolactic acid monomer at 170 ℃ under 5kPa for dehydration for 5-10 hours, adding 1wt% of stannous octoate as a catalyst, distilling lactide at 180 ℃ under 0.5kPa, and condensing to obtain crude lactide;
(2) Washing and recrystallizing the crude lactide in sequence to obtain purified levorotatory lactide;
(3) Adding 0.5wt% of zinc acetylacetonate as a catalyst into the purified levorotatory lactide, heating to 100 ℃ in nitrogen atmosphere, and maintaining for 8 hours to perform ring-opening polymerization reaction; centrifuging the product obtained by the ring-opening polymerization reaction, pouring the supernatant into a methanol solution, filtering, washing and drying after the product is fully separated out, thus obtaining the polylactic acid.
2. The preparation of the collagen solution comprises the following steps:
(1) Fresh animal tissues are soaked in 10% glacial acetic acid for 180 hours, then horny layer and fat layer are removed, and 0.3wt% of pepsin is added into 0.5M glacial acetic acid solution for enzymolysis and digestion for 96 hours, so that collagen enzymolysis liquid is obtained.
(2) And inactivating, redissolving, salting out and purifying the collagen enzymolysis liquid to obtain a collagen solution.
3. The preparation of the heart stent comprises the following steps:
(1) Dissolving the prepared polylactic acid in 1, 4-dioxane, and fully stirring for later use;
(2) Adding the polylactic acid solution into the collagen solution, fully stirring and mixing, and adding a cross-linking agent to carry out a cross-linking reaction at room temperature to prepare printing slurry; the mass ratio of the polylactic acid in the polylactic acid solution to the collagen in the collagen solution is 0.02:1, a step of; the temperature of the crosslinking reaction is 15 ℃; the time of the crosslinking reaction is 8 hours;
(3) Forming the printing slurry into a heart stent by adopting a 3D printing technology, and freeze-drying the heart stent; immersing the freeze-dried heart stent into a drug solution with a preset concentration, and taking out and drying after full immersion.
Example 3
1. The preparation of polylactic acid comprises the following steps:
(1) Heating and decompressing a levolactic acid monomer at 220 ℃ under 5kPa for dehydration for 10 hours, adding 10wt% of stannous octoate as a catalyst, distilling lactide at 220 ℃ under 0.5kPa, and condensing to obtain crude lactide;
(2) Washing and recrystallizing the crude lactide in sequence to obtain purified levorotatory lactide;
(3) Adding 1.5wt% of zinc acetylacetonate as a catalyst into the purified levorotatory lactide, heating to 160 ℃ in a nitrogen atmosphere, and maintaining for 48 hours to perform ring-opening polymerization reaction; centrifuging the product obtained by the ring-opening polymerization reaction, pouring the supernatant into a methanol solution, filtering, washing and drying after the product is fully separated out, thus obtaining the polylactic acid.
2. The preparation of the collagen solution comprises the following steps:
(1) Fresh animal tissues are soaked in 10% glacial acetic acid for 270 hours, then horny layer and fat layer are removed, and 3wt% of pepsin is added into 0.5M glacial acetic acid solution for enzymolysis and digestion for 120 hours, so that collagen enzymolysis liquid is obtained.
(2) And inactivating, redissolving, salting out and purifying the collagen enzymolysis liquid to obtain a collagen solution.
3. The preparation of the heart stent comprises the following steps:
(1) Dissolving the prepared polylactic acid in 1, 4-dioxane, and fully stirring for later use;
(2) Adding the polylactic acid solution into the collagen solution, fully stirring and mixing, and adding a cross-linking agent to carry out a cross-linking reaction at room temperature to prepare printing slurry; the mass ratio of the polylactic acid in the polylactic acid solution to the collagen in the collagen solution is 0.2:1, a step of; the temperature of the crosslinking reaction is 30 ℃; the time of the crosslinking reaction is 24 hours;
(3) Forming the printing slurry into a heart stent by adopting a 3D printing technology, and freeze-drying the heart stent; immersing the freeze-dried heart stent into a drug solution with a preset concentration, and taking out and drying after full immersion.
Example 4
1. The preparation of polylactic acid comprises the following steps:
(1) Heating and decompressing a levolactic acid monomer at 180 ℃ under 5kPa for dehydration for 6 hours, adding 3wt% of stannous octoate as a catalyst, distilling lactide at 190 ℃ under 0.5kPa, and condensing to obtain crude lactide;
(2) Washing and recrystallizing the crude lactide in sequence to obtain purified levorotatory lactide;
(3) Adding 0.8wt% of zinc acetylacetonate as a catalyst into the purified levorotatory lactide, heating to 120 ℃ in nitrogen atmosphere, and maintaining for 14 hours to perform ring-opening polymerization reaction; centrifuging the product obtained by the ring-opening polymerization reaction, pouring the supernatant into a methanol solution, filtering, washing and drying after the product is fully separated out, thus obtaining the polylactic acid.
2. The preparation of the collagen solution comprises the following steps:
(1) Fresh animal tissues are soaked in 10% glacial acetic acid for 200 hours, then horny layer and fat layer are removed, and 0.8wt% pepsin is added into 0.5M glacial acetic acid solution for enzymolysis and digestion for 105 hours, so that collagen enzymolysis liquid is obtained.
(2) And inactivating, redissolving, salting out and purifying the collagen enzymolysis liquid to obtain a collagen solution.
3. The preparation of the heart stent comprises the following steps:
(1) Dissolving the prepared polylactic acid in 1, 4-dioxane, and fully stirring for later use;
(2) Adding the polylactic acid solution into the collagen solution, fully stirring and mixing, and adding a cross-linking agent to carry out a cross-linking reaction at room temperature to prepare printing slurry; the mass ratio of the polylactic acid in the polylactic acid solution to the collagen in the collagen solution is 0.07:1, a step of; the temperature of the crosslinking reaction is 19 ℃; the time of the crosslinking reaction is 13h;
(3) Forming the printing slurry into a heart stent by adopting a 3D printing technology, and freeze-drying the heart stent; immersing the freeze-dried heart stent into a drug solution with a preset concentration, and taking out and drying after full immersion.
Example 5
1. The preparation of polylactic acid comprises the following steps:
(1) Heating and decompressing a levolactic acid monomer at 210 ℃ under 5kPa for dehydration for 8 hours, adding 9wt% of stannous octoate as a catalyst, distilling lactide at 210 ℃ under 0.5kPa, and condensing to obtain crude lactide;
(2) Washing and recrystallizing the crude lactide in sequence to obtain purified levorotatory lactide;
(3) Adding 1.2wt% of zinc acetylacetonate as a catalyst into the purified levorotatory lactide, heating to 140 ℃ in nitrogen atmosphere, and maintaining for 40 hours to perform ring-opening polymerization reaction; centrifuging the product obtained by the ring-opening polymerization reaction, pouring the supernatant into a methanol solution, filtering, washing and drying after the product is fully separated out, thus obtaining the polylactic acid.
2. The preparation of the collagen solution comprises the following steps:
(1) Fresh animal tissues are soaked in 10% glacial acetic acid for 250 hours, then horny layer and fat layer are removed, 2.8wt% pepsin is added into 0.5M glacial acetic acid solution for enzymolysis and digestion for 115 hours, and then collagen enzymolysis liquid is obtained.
(2) And inactivating, redissolving, salting out and purifying the collagen enzymolysis liquid to obtain a collagen solution.
3. The preparation of the heart stent comprises the following steps:
(1) Dissolving the prepared polylactic acid in 1, 4-dioxane, and fully stirring for later use;
(2) Adding the polylactic acid solution into the collagen solution, fully stirring and mixing, and adding a cross-linking agent to carry out a cross-linking reaction at room temperature to prepare printing slurry; the mass ratio of the polylactic acid in the polylactic acid solution to the collagen in the collagen solution is 0.15:1, a step of; the temperature of the crosslinking reaction is 25 ℃; the time of the crosslinking reaction is 20 hours;
(3) Forming the printing slurry into a heart stent by adopting a 3D printing technology, and freeze-drying the heart stent; immersing the freeze-dried heart stent into a drug solution with a preset concentration, and taking out and drying after full immersion.
Comparative example 1
1. Polylactic acid was prepared as in example 1;
2. preparation of collagen solution the same as in example 1;
3. the preparation of the heart stent comprises the following steps:
(1) As in example 1;
(2) No crosslinker was added, the remainder being the same as in example 1;
(3) As in example 1.
Comparative example 2
The polylactic acid used in this comparative example had a molecular weight of 150 ten thousand, and the preparation of a collagen solution and the preparation of a cardiac scaffold were the same as in example 1.
Comparative example 3
The temperature of the crosslinking reaction in this comparative example was 45℃and the rest was the same as in example 1.
Experimental example
The performance of the cardiac stents of each example and comparative example was tested and the results are shown in table 1.
TABLE 1
As can be seen from Table 1, the high biosafety heart stent prepared in examples 1 to 5 has higher radial strength and porosity, and can be completely degraded within 24 months, so that an effective supporting effect on blood vessels is achieved in early stage, safety of the implanted part of the stent is ensured by using excellent drug carrying capacity, and the stent is completely degraded after the recovery capacity of the blood vessels, the risk of thrombus and stent restenosis in the stent in later stage is effectively reduced, and the high biosafety heart stent has higher biosafety and can meet the requirements of practical application.
Examples 1 to 5 and comparative example 2
As can be seen from comparative examples 1 to 5 and comparative example 2, as the molecular weight of polylactic acid increases, the radial strength of the produced heart stent increases, but the porosity decreases and the degradation rate decreases. Compared with the example, the comparative example 2 has higher radial strength, but has low porosity, long degradation time, small drug-loading capacity, easy initiation of thrombus in the stent and restenosis of the stent in the later period of use of the stent part, and low biocompatibility. Therefore, in order to ensure that the cardiac stent has comprehensive and better performance, the molecular weight of the polylactic acid is preferably 30-100 ten thousand, and the prepared cardiac stent can have relatively higher radial strength, porosity and proper degradation rate at the same time, and has higher biological safety.
Example 1 and comparative example 1
As can be seen from comparative example 1 and comparative example 1, in which a crosslinking agent was not added under the same polylactic acid preparation process and polylactic acid molecular weight, the radial strength was low, the porosity was low, and the degradation rate was excessively fast, and the degradation period was not determined. Compared with the example 1, the heart stent prepared by the invention has low radial strength, low porosity and uncertain degradation time, so that the heart stent prepared by the invention has comprehensive better performance, and the prepared heart stent can have relatively higher radial strength, porosity and proper degradation rate and higher biosafety at the same time by adding the cross-linking agent.
Example 1 and comparative example 3
As can be seen from the comparison of example 1 and comparative example 3, the crosslinking reaction temperature of the examples is higher than that of comparative example 3, the radial strength is too high, the porosity is lower, and the degradation time is longer. Compared with the example, the comparative example 3 has higher radial strength, but has low porosity and long degradation period, and is easy to cause problems of thrombus in the stent, restenosis of the stent and the like at the later period of stent use, and has low biocompatibility. Therefore, in order to ensure that the cardiac stent has comprehensive better performance, the crosslinking reaction temperature of the invention is preferably 15-30 ℃, and the prepared cardiac stent can have relatively higher radial strength, porosity and proper degradation rate at the same time, and has higher biosafety.
In summary, the invention prepares polylactic acid with proper molecular weight through coordination ring-opening polymerization, and adds a cross-linking agent into a mixed system of polylactic acid solution and collagen solution to carry out cross-linking reaction, thus obtaining printing slurry; and printing and forming the printing slurry into the heart stent. Through the mode, the molecular weight of the polylactic acid can be regulated, so that the polylactic acid has better mechanical property and degradation property; the heart stent prepared by the method has higher radial strength, proper porosity and degradation time, and can meet the requirements of practical application.
While the invention has been illustrated and described with reference to specific embodiments, it is to be understood that the above embodiments are merely illustrative of the technical aspects of the invention and not restrictive thereof; those of ordinary skill in the art will appreciate that: modifications may be made to the technical solutions described in the foregoing embodiments, or equivalents may be substituted for some or all of the technical features thereof, without departing from the spirit and scope of the present invention; such modifications and substitutions do not depart from the spirit of the corresponding technical solutions; it is therefore intended to cover in the appended claims all such alternatives and modifications as fall within the scope of the invention.
Claims (10)
1. The preparation method of the heart stent is characterized by comprising the following steps of:
adding a cross-linking agent into a mixed system of a polylactic acid solution and a collagen solution, and then performing a cross-linking reaction to obtain printing slurry; printing and forming the printing paste into the heart stent;
wherein the molecular weight of the polylactic acid in the polylactic acid solution is 30 ten thousand to 100 ten thousand.
2. The method for preparing a cardiac stent according to claim 1, wherein the method for preparing polylactic acid in the polylactic acid solution comprises the following steps:
adding stannous octoate into the dehydrated levolactic acid monomer, and then carrying out distillation, condensation, water washing and recrystallization to obtain the levolactic acid;
carrying out ring-opening polymerization reaction on the mixed system of the levorotatory lactide and the zinc acetylacetonate in a protective atmosphere; centrifuging the product of the ring-opening polymerization reaction, uniformly mixing the supernatant obtained by the centrifugation with methanol, and then filtering, washing and drying;
preferably, the mass ratio of the levolactic acid monomer to the stannous octoate is 1:1 to 10;
preferably, the mass ratio of the levorotatory lactide to the zinc acetylacetonate is 1:0.5 to 1.5.
3. The method for preparing a cardiac stent according to claim 2, wherein the temperature of the distillation is 180-220 ℃;
preferably, the pressure of the distillation is 0.1 to 1.0kPa.
4. The method for preparing a cardiac stent according to claim 2, wherein the temperature of the ring-opening polymerization reaction is 100 to 160 ℃;
preferably, the ring-opening polymerization reaction time is 8 to 48 hours.
5. The method for preparing a cardiac stent according to claim 1, wherein the concentration of polylactic acid in the polylactic acid solution is 0.01-0.2 mg/ml;
preferably, the concentration of the collagen in the collagen solution is 0.3-1.0 mg/ml;
preferably, the mass ratio of the polylactic acid in the polylactic acid solution to the collagen in the collagen solution is 0.02-0.2: 1.
6. the method for preparing a cardiac stent according to claim 1, wherein the temperature of the crosslinking reaction is 15-30 ℃;
preferably, the time of the crosslinking reaction is 8 to 24 hours.
7. The method of preparing a cardiac stent of claim 1, wherein the cross-linking agent comprises: 1-ethyl- (3-dimethylaminopropyl) carbodiimide and/or N-hydroxysuccinimide;
preferably, the concentration of the 1-ethyl- (3-dimethylaminopropyl) carbodiimide is 10 to 80mM;
preferably, the concentration of the N-hydroxysuccinimide is 2 to 50mM.
8. The method for producing a cardiac stent according to any one of claims 1 to 7, further comprising: freeze-drying and drug-coating the cardiac stent;
preferably, the drug-coated drug types include: at least one of rapamycin, paclitaxel, heparin, or aspirin;
preferably, the drug-coated drug concentration is 0.08-0.12 g/mL.
9. A cardiac stent prepared by the method for preparing a cardiac stent according to any one of claims 1 to 8.
10. Use of a cardiac stent according to claim 9 in the manufacture of a medicament or medical device for the treatment or prophylaxis of coronary artery disease.
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